Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability

Background: Late Na+ current (I-NaL) in human and dog hearts has been implicated in abnormal repolarization associated with heart failure (HF). HF slows inactivation gating of late Na+ channels, which could contribute to these abnormalities. Aims: To test how altered gating affects I-NaL time course, Na+ influx, and action potential (AP) repolarization. Methods: I-NaL and AP were measured by patch clamp in left ventricular cardiomyocytes from normal and failing hearts of humans and dogs. Canine HF was induced by coronary microembolization. Results: INaL decay was slower and INaL density was greater in failing hearts than in normal hearts at 24 degrees C (human hearts: tau=659 16 vs. 529 +/- 21 ms; n=16 and 4 hearts, respectively; mean +/- SEM; p < 0.002; dog hearts: 561 +/- 13 vs. 420 +/- 17 ms; and 0.307 +/- 0.014 vs. 0.235 +/- 0.019 pA/pF; n=25 and 14 hearts, respectively; p < 0.005) and at 37 degrees C this difference tended to increase. These INaL changes resulted in much greater (53.6%) total Na+ influx in failing cardiomyocytes. I-NaL was sensitive to cadmium but not to cyanide and exhibited low sensitivity to saxitoxin (IC50=62 nM) or tetrodotoxin (IC50 = 1.2 mu M), tested in dogs. A 50% I-NaL inhibition by toxins or passing current opposite to I-NaL, decreased beat-to-beat AP variability and eliminated early afterdepolarizations in failing cardiomyocytes. Conclusions: Chronic HF leads to larger and slower IN L generated mainly by the cardiac-type Na+ channel isoform, contributing to larger Na+ influx and AP duration variability. Interventions designed to reduce/normalize IN L represent a potential cardioprotective mechanism in HF via reduction of related Na+ and Ca2+ overload and improvement of repolarization. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.